Cathepsins B and D drive hepatic stellate cell proliferation and promote their fibrogenic potential

El pdf del artículo es el manuscrito de autor.-- PubMed: PMCID:PMC2670444Cathepsins have been best characterized in tumorigenesis and cell death and implicated in liver fibrosis; however, whether cathepsins directly regulate hepatic stellate cell (HSC) activation and proliferation, hence modulating their fibrogenic potential, is largely unknown. Here, we show that expression of cathepsin B (CtsB) and cathepsin D (CtsD) is negligible in quiescent HSCs but parallels the increase of -smooth muscle actin and transforming growth factor- during in vitro mouse HSC activation. Both cathepsins are necessary for HSC transdifferentiation into myofibroblasts, because their silencing or inhibition decreasedHSC proliferation and the expression of phenotypicmarkers ofHSC activation, with similar results observed with the human HSC cell line LX2. CtsB inhibition blunted AKT phosphorylation in activated HSCs in response to platelet-derived growth factor.Moreover, during in vivo liver fibrogenesis caused by CCl4 administration, CtsB expression increased in HSCs but not in hepatocytes, and its inactivation mitigated CCl4-induced inflammation, HSC activation, and collagen deposition. Conclusion: These findings support a critical role for cathepsins inHSC activation, suggesting that the antagonismof cathepsins inHSCsmay be of relevance for the treatment of liver fibrosis.Financial support: The work was supported by CIBEREHD and grant PI070193 (Instituto de Salud Carlos III); by grant SAF2006-06780 (Plan Nacional de I+D), Spain; and by grant P50-AA-11999 (Research Center for Liver and Pancreatic Diseases, US National Institute on Alcohol Abuse and Alcoholism).Peer reviewe

Satellite Survival in Highly Resolved Milky Way Class Halos

Surprisingly little is known about the origin and evolution of the Milky Way's satellite galaxy companions. UV photoionisation, supernova feedback and interactions with the larger host halo are all thought to play a role in shaping the population of satellites that we observe today, but there is still no consensus as to which of these effects, if any, dominates. In this paper, we revisit the issue by re-simulating a Milky Way class dark matter (DM) halo with unprecedented resolution. Our set of cosmological hydrodynamic Adaptive Mesh Refinement (AMR) simulations, called the Nut suite, allows us to investigate the effect of supernova feedback and UV photoionisation at high redshift with sub-parsec resolution. We subsequently follow the effect of interactions with the Milky Way-like halo using a lower spatial resolution (50pc) version of the simulation down to z=0. This latter produces a population of simulated satellites that we compare to the observed satellites of the Milky Way and M31. We find that supernova feedback reduces star formation in the least massive satellites but enhances it in the more massive ones. Photoionisation appears to play a very minor role in suppressing star and galaxy formation in all progenitors of satellite halos. By far the largest effect on the satellite population is found to be the mass of the host and whether gas cooling is included in the simulation or not. Indeed, inclusion of gas cooling dramatically reduces the number of satellites captured at high redshift which survive down to z=0.Comment: 22 pages, 16 figures, accepted for publication in MNRA

Luminosity function and radial distribution of Milky Way Satellites in a LCDM Universe

We study the luminosity function and the radial distribution of satellite galaxies within Milky Way sized haloes as predicted in Cold Dark Matter based models of galaxy formation, making use of numerical N-body techniques as well as three different semi-analytic model (SAMs) galaxy formation codes. We extract merger trees from very high-resolution dissipationless simulations of four Galaxy-sized DM haloes, and use these as common input for the semi-analytic models. We present a detailed comparison of our predictions with the observational data recently obtained on the Milky Way satellite luminosity function (LF). We find that semi-analytic models with rather standard astrophysical ingredients are able to reproduce the observed luminosity function over six orders of magnitude in luminosity, down to magnitudes as faint as M_V=-2. We also perform a comparison with the actual observed number of satellites as a function of luminosity, by applying the selection criteria of the SDSS survey to our simulations instead of correcting the observations for incompleteness. Using this approach we again find good agreement for both the luminosity and radial distributions of MW satellites. We investigate which physical processes in our models are responsible for shaping the predicted satellite LF, and find that tidal destruction, suppression of gas infall by a photo-ionizing background, and supernova feedback all make important contributions. We conclude that the number and luminosity of Milky Way satellites can be naturally accounted for within the (Lambda) Cold Dark Matter paradigm, and this should no longer be considered a problem.Comment: 16 pages, 15 figures, paper shortened, statistical analysis improved, new title, accepted for publication in MNRA

Performance in Physical Education and Health Impairment 30 Years Later—A Community Based Cohort Study

Objective: A main purpose of physical education (PE) in school is to promote future health. However, there is very limited evidence of the effects of PE on the adult health. We hypothesized that a low performance in PE was associated with an increased risk of health impairment by middle age. Methods: We performed a cohort study in a community-based setting in Sweden spanning over three decades. We followed up on 1712 of 2225 students (76.9%) who in 1974–1976 graduated with a grade in PE after 9 years of education (mean subject age 16 years). The grade in PE (compulsory subject) was retrieved from municipal archives. We defined three proxies for health impairment: total number of visits to primary care physicians in 2003–2007, having been hospitalized 2003–2007, and total number of days with sick leave in 2004–2007. Using binomial regression models, we adjusted the risk estimates for level of education and occupation. Subjects with an average grade in PE served as reference category. Results: In both the crude and adjusted model, women with a low grade in PE had more physician visits (adjusted IRR 1.30, 95 % confidence interval 1.06–1.60) and an increased number of days with sick leave (adjusted IRR 1.44, 1.05–1.95). An increased, although not significant, risk was also observed for having received in-patient care (adjusted RR 1.26; 0.88–1.80). No significant results or similar pattern were observed in men. Conclusion: Women with a low grade in PE in adolescence seem to have an increased risk of health impairment by middl

The Nutrition and Enjoyable Activity for Teen Girls (NEAT girls) randomized controlled trial for adolescent girls from disadvantaged secondary schools: rationale, study protocol, and baseline results

Background: Child and adolescent obesity predisposes individuals to an increased risk of morbidity and mortality from a range of lifestyle diseases. Although there is some evidence to suggest that rates of pediatric obesity have leveled off in recent years, this has not been the case among youth from low socioeconomic backgrounds. The purpose of this paper is to report the rationale, study design and baseline findings of a school-based obesity prevention program for low-active adolescent girls from disadvantaged secondary schools. Methods/Design: The Nutrition and Enjoyable Activity for Teen Girls (NEAT Girls) intervention will be evaluated using a group randomized controlled trial. NEAT Girls is a 12-month multi-component school-based intervention developed in reference to Social Cognitive Theory and includes enhanced school sport sessions, interactive seminars, nutrition workshops, lunch-time physical activity (PA) sessions, PA and nutrition handbooks, parent newsletters, pedometers for self-monitoring and text messaging for social support. The following variables were assessed at baseline and will be completed again at 12- and 24-months: adiposity, objectively measured PA, muscular fitness, time spent in sedentary behaviors, dietary intake, PA and nutrition social-cognitive mediators, physical self-perception and global self-esteem. Statistical analyses will follow intention-to-treat principles and hypothesized mediators of PA and nutrition behavior change will be explored. Discussion: NEAT Girls is an innovative intervention targeting low-active girls using evidence-based behavior change strategies and nutrition and PA messages and has the potential to prevent unhealthy weight gain and reduce the decline in physical activity and poor dietary habits associated with low socio-economic status. Few studies have reported the long-term effects of school-based obesity prevention programs and the current study has the potential to make an important contribution to the field

Impact of Marine Drugs on Animal Reproductive Processes

The discovery and description of bioactive substances from natural sources has been a research topic for the last 50 years. In this respect, marine animals have been used to extract many new compounds exerting different actions. Reproduction is a complex process whose main steps are the production and maturation of gametes, their activation, the fertilisation and the beginning of development. In the literature it has been shown that many substances extracted from marine organisms may have profound influence on the reproductive behaviour, function and reproductive strategies and survival of species. However, despite the central importance of reproduction and thus the maintenance of species, there are still few studies on how reproductive mechanisms are impacted by marine bioactive drugs. At present, studies in either marine and terrestrial animals have been particularly important in identifying what specific fine reproductive mechanisms are affected by marine-derived substances. In this review we describe the main steps of the biology of reproduction and the impact of substances from marine environment and organisms on the reproductive processes

VCL-ALK renal cell carcinoma in adult patient without sickle cell trait

Anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC) is a provisional renal cell carcinoma subtype with a growing list of published fusion partners. VCL-ALK gene fusion represents an uncommon fusion partner (only 6 reported cases), almost always associated with sickle cell trait and typically in a pediatric population. Herein, we report only the second case of VCL-ALK gene fusion ALK-RCC from a 31-year-old female without associated sickle cell trait, and also only the third reported case occurring in an adult patient. The tumor (measuring 8.5 cm and confined to the kidney) demonstrated mostly solid growth, pleomorphic nuclei, variably rhabdoid to vacuolated cytoplasm, and showed diffuse strong immunoreactivity for both PAX8 and ALK stains. Gene panel sequencing confirmed VCL-ALK gene fusion in the tumor. This study expands the clinical framework for diagnostic consideration of this rare tumor with potential targeted pharmacotherapy